Effects of N-omega-nitro-L-arginine methyl ester on the endotoxin-induced disseminated intravascular coagulation in porcine septic shock

Objectives: Nitric oxide is known to prevent platelet aggregation and clot formation. Inhibitors of nitric oxide synthase might promote or enhance endotoxin disseminated intravascular coagulation. The present study was designed to evaluate the effects of the arginine analog, N-omega-nitro-L-arginine methyl ester (L-NAME), on the endotoxin-induced disseminated intravascular coagulation in a porcine model of septic shock. Design: Prospective, comparative, experimental study. Setting: Laboratory at a large university hospital. Subjects: Sixteen female piglets, weighing 20 to 28 kg. Interventions: Three groups of animals were studied: a control group (n = 6); a lipopolysaccharide (LPS)-treated group (n = 5) receiving Escherichia coli endotoxin (5 mu g/kg/min over 30 mins); and an LPS + L-NAME group (n = 5) receiving endotoxin and, 1 hr after, a bolus of L-NAME (25 mg/kg). Measurements and Main Results: Hemodynamic changes, usual coagulation parameters, and plasma concentrations of thrombin-antithrombin complexes, antithrombin III activity (AT III), tissue plasminogen activator, plasminogen activator inhibitor type 1, and von Willebrand factor were measured at baseline, and at 30, 60, 90, 120, 180, 240, and 300 mins. After euthanasia or death, lungs and kidneys were withdrawn for histologic study. The extent of microvascular thrombosis was assessed by a semiquantitative disseminated intravascular coagulation score. In both septic endotoxin groups, administration of LPS resulted in hemodynamic changes typical of severe septic shock, with disseminated intravascular coagulation and histologic changes characterized by adult respiratory distress syndrome and kidney microthrombosis. L-NAME administration normalized mean arterial pressure with a dramatic increase in systemic vascular resistances and a marked decrease in cardiac index. The changes in usual coagulation parameters, AT HI, tissue plasminogen activator, and plasminogen-activator inhibitor type 1 concentrations were not different between both septic groups. However, in the LPS + L-NAME group, thrombin-antithrombin complexes and von Willebrand factor were higher and associated with a higher histologic disseminated intravascular coagulation score, Conclusion: in this model of endotoxin septic shock, L-NAME administration resulted in histologic and coagulation changes consistent with an increased activation of intravascular coagulation.